The Gene That Knows Left From Right

The human body is a marvel of symmetry--two ears, two eyes, two arms, two legs, each one a mirror image of its opposite number--but also of asymmetry. Each of us has just one heart, tucked into the left side of our chest; one spleen, on the left side of our abdomen; one stomach, mostly on the left; and one liver, mostly on the right. While researchers know a good deal about how a developing embryo makes, say, mirror-image arms, they know next to nothing about how that same embryo knows left from right and which organs go where. And they have been equally puzzled by a condition that affects one out of every 10,000 people, a condition called situs inversus, in which the internal organs end up on the wrong side.

Now developmental geneticist Paul Overbeek and his colleagues at the Baylor College of Medicine in Houston have uncovered a gene in mice that, when mutated, inevitably results in situs inversus. Their discovery may help us understand not only the medical condition--situs inversus sometimes leads to dangerous missed connections in the cardiovascular system--but also how a normal developing embryo tells left from right.

Overbeek and his co-workers weren’t looking for a situs inversus gene. They were just trying to practice some gene therapy techniques by seeing if they could convert albino mice into colored ones. The researchers injected a gene essential to the production of the pigment melanin into the single-cell embryo of an albino mouse. Later they inbred that mouse’s offspring, half of which carried the gene on one chromosome of a chromosome pair. Classic Mendelian genetics told them that roughly a quarter of the grandchildren should carry the gene on both chromosomes--should be homozygous, in the language of genetics--and should therefore be colored.

But the mice never got a chance to acquire color. The first thing we noticed, says Overbeek, was that we were losing about 25 percent of the grandchildren within a week after they were born. Something was killing the homozygous mice, and it didn’t take long to find out what. We placed every mouse so you could see its stomach, says Overbeek. Their skin is somewhat transparent when they’re less than a week old; since milk is white, once it’s in the stomach you can see the white stomach through the skin. We realized that the sick mice all had to be turned onto the opposite side from the normal mice to show their stomachs. When we took a look inside, we found everything was reversed.

By pure chance, Overbeek explains, the melanin-related gene that his group had injected into the albino mouse embryo had inserted itself into a completely unrelated gene--one that is somehow involved in specifying what goes on which side of the body. An unfamiliar stretch of DNA in the middle of a gene wrecks that gene’s ability to get its message read. So in Overbeek’s mice, it seems, whatever protein the gene coded for went unproduced, whatever function the protein had went undone, and the stomach, heart, liver, and spleen all wound up in the wrong place. Somehow, too, the kidneys and pancreas were damaged, and that damage is apparently what killed the mice.

Overbeek’s isn’t the first genetic link to situs inversus: in the late 1950s a gene was found that, when mutated, resulted in situs inversus about half the time. Overbeek’s mutated gene, though, causes the condition all the time and thus appears to be particularly important for left-right determination. The connection between the two genes is unclear, says Overbeek. One may regulate the other.

Overbeek and his colleagues have already located the gene on a particular mouse chromosome and are now trying to pin down its structure. That will tell them something about the structure of the protein the gene encodes, how the protein works, and when and where it is produced as the gene gets expressed, or turned on. Is the gene expressed everywhere, or just on the left side of the embryo or just on the right side? Overbeek wonders. And when does it get expressed?

These questions will take Overbeek far from the gene-transfer experiment he started with. We think there are at least 100,000 genes, he points out, so the chances of this happening were literally one in 100,000.